TDP-43 expression in mouse models of amyotrophic lateral sclerosis and spinal muscular atrophy.
BACKGROUND
Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS) pathology. Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease. Here, we characterise TDP-43 localisation, expression levels and post-translational modifications in mouse models of ALS and spinal muscular atrophy (SMA).


RESULTS
TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1G93A mice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords.


CONCLUSIONS
These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.
Turner
Bradley J
BJ
University of Oxford, MRC Functional Genetics Unit, Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford, OX1 3QX, UK. bradley.turner@florey.edu.au
Bäumer
Dirk
D
Parkinson
Nicholas J
NJ
Scaber
Jakub
J
Ansorge
Olaf
O
Talbot
Kevin
K
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000870:Anterior Horn Cells / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D020541:Coiled Bodies / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D054875:Ubiquitination
D004268:DNA-Binding Proteins; D055533:Survival of Motor Neuron 1 Protein; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase